The Association of Brd2 with Juvenile Myoclonic Epilepsy
The Association of BRD2 with Juvenile Myoclonic Epilepsy
Abstract
Idiopathic generalized epilepsy (IGE) constitutes a variety of epileptic disorders in humans, the most common being juvenile myoclonic epilepsy (JME). There is strong evidence that JME can be caused by a faulty genetic variation in the human gene bromodomain-containing protein 2 (BRD2). For this reason, many studies on BRD2 homologues have been conducted to determine the function of this protein. Studies on human BRD2 have revealed that certain polymorphisms in non-coding regions near the promoter are associated with JME. Knock-out experiments in mice reveal that the Brd2 deficient mice are smaller, display embryonic lethality, have slower cell proliferation in mouse embryonic fibroblasts and display defects during neurogenesis. Furthermore, studies in zebrafish confirm that Brd2 has a role in the development of vertebrates.
Introduction
Juvenile myoclonic epilepsy (JME) is a form of idiopathic generalized epilepsy (IGE). JME is characterized by monoclonic seizures, which consists of small jerks of the arms, shoulders and sometimes legs. It accounts for 26% of all IGEs and begins by late childhood or early adolescence1. Many forms of IGEs have been linked to a single genetic mutation that follows Mendelian Inheritance; however it appears that there is a more complex mechanism that causes JME2,3. Another insight on the causation of this disorder is that there are many genes associated with JME, in particular the EJM1 locus on chromosome 6, as shown by Greenberg and collegues by linkage analysis4. EJM1 was later found to include bromodomain-containing protein 2 (BRD2)1,3,5. BRD2 has been characterized as a transcriptional activator of proteins involved in the cell cycle6. This has generated an interest in determining the function of BRD2 in embryogenesis. Researchers studying orthologs of BRD2 have discovered a role in brain development7,8,9 and this knowledge might help
Abstract
Idiopathic generalized epilepsy (IGE) constitutes a variety of epileptic disorders in humans, the most common being juvenile myoclonic epilepsy (JME). There is strong evidence that JME can be caused by a faulty genetic variation in the human gene bromodomain-containing protein 2 (BRD2). For this reason, many studies on BRD2 homologues have been conducted to determine the function of this protein. Studies on human BRD2 have revealed that certain polymorphisms in non-coding regions near the promoter are associated with JME. Knock-out experiments in mice reveal that the Brd2 deficient mice are smaller, display embryonic lethality, have slower cell proliferation in mouse embryonic fibroblasts and display defects during neurogenesis. Furthermore, studies in zebrafish confirm that Brd2 has a role in the development of vertebrates.
Introduction
Juvenile myoclonic epilepsy (JME) is a form of idiopathic generalized epilepsy (IGE). JME is characterized by monoclonic seizures, which consists of small jerks of the arms, shoulders and sometimes legs. It accounts for 26% of all IGEs and begins by late childhood or early adolescence1. Many forms of IGEs have been linked to a single genetic mutation that follows Mendelian Inheritance; however it appears that there is a more complex mechanism that causes JME2,3. Another insight on the causation of this disorder is that there are many genes associated with JME, in particular the EJM1 locus on chromosome 6, as shown by Greenberg and collegues by linkage analysis4. EJM1 was later found to include bromodomain-containing protein 2 (BRD2)1,3,5. BRD2 has been characterized as a transcriptional activator of proteins involved in the cell cycle6. This has generated an interest in determining the function of BRD2 in embryogenesis. Researchers studying orthologs of BRD2 have discovered a role in brain development7,8,9 and this knowledge might help
References: . 2. Mulley J, Scheffer I, Harkin L, Berkovic S, Dibbens L. 2005. Susceptibility genes for complex epilepsy. Human Molecular Genetics 14: 243–249 . . 5. Lorenz S, Taylor K, Gehrmann A, Becker T, Muhle H, Gresch M, Tauer U, Sander T, Stephani U. 2006. Association of BRD2 polymorphisms with photoparoxysmal response. Neuroscience Letters 400:135–139. . 6. Denis G, Vaziri C, Guo N, Faller D. 2000. RING3 kinase transactivates promoters of cell cycle regulatory genes through E2F. Cell Growth & Differentiation 11:417–424. Scheffer, IE., Berkovic, SF., Macdonald, RL., Mulley, JC. 2004. GABRD encoding a protein for extra- or perisynaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Human Molecular Genetics 13: 1315-1319. . 8. Gyuris A, Donovan DJ, Seymour KA, Lovasco LA, Smilowitz NR, Halperin AL, Klysik JE, Freiman RN. 2009. The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesis. Biochimica et Biophysica Acta 1789:413–421. . 9. Shang E, Wang X, Wen D, Greenberg D, Wolgemuth DJ. 2009. Double bromodomain-containing gene Brd2 is essential for embryonic development in mouse. Developmental Dynamics 238:908-917. . 10. Pal DK, Evgrafov OV, Tabares P, Zhang F, Durner M, Greenberg DA. 2003. BRD2 (RING3) is a probable major susceptibility gene for common juvenile myoclonic epilepsy. The American Journal of Human Genetics 73:261–270. . 11. Tae W, Hong S, Joo E, Han S, Cho J, Seo D, Lee J, Kim I, Byun H, Kim S. 2006. Structural Brain Abnormalities in Juvenile Myoclonic Epilepsy Patients: Volumetry and Voxel-Based Morphometry. Korean Journal of Radiology 7:162-172. . 12. Cossette P, Liu L, Brisebois K., Dong H., Lortie A., Vanasse A., Saint-Hilaire J., Carmant L., Verner A., Lu W., Wang Y., Rouleau A. 2002. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nature Genetics 31:184:189. Scheffer, IE., Berkovic, SF., Macdonald, RL., Mulley, JC. 2004. GABRD encoding a protein for extra- or perisynaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Human Molecular Genetics 13: 1315-1319. . 16. Kanno T, Kanno Y, Siegel R, Jang M, Lenardo M, Ozato K. 2004. Selective recognition of acetylated histones by bromodomain proteins visualized in living cells. Molecular Cell 13:33–43. . 17. The GeneCards Human Gene Database, Weizmann Institute of Science. “Bromodomain-containing 2,” November 12, 2009. URL: http://www.genecards.org/cgi-bin/carddisp.pl?gene=BRD2 -----------------------